Dry eye, which is also called xerophthalmia or dry eye syndrome, is a disease in which a reduction or impairment in tear secretory function of a lacrimal gland, or the like causes a quantitative and/or qualitative abnormality in tears, resulting in an impairment in an ocular surface, that is, cornea and conjunctiva. As a cause of the reduction or impairment in tear secretory function of the lacrimal gland, there are known, for example, video display terminal work (VDT work), aging, and a disease involving inflammation in the lacrimal gland. As such disease, there are known, for example, an autoimmune disorder, such as Sjögren's syndrome, keratoconjunctivitis sicca, Stevens-Johnson syndrome, and marginal blepharitis. When inflammation occurs in the lacrimal gland, inflammatory cells, such as lymphocytes, infiltrate the lacrimal gland to cause the reduction or impairment in tear secretory function of the lacrimal gland. It is said that there are 8,000,000 or more dry eye patients, including potential patients, in Japan, and the increase in dry eye has even become a social problem.
As a method of ameliorating dry eye, a method involving administering artificial tears is generally used. However, the method is only a symptomatic treatment. In addition, its effect is temporary, and hence the method has been troublesome to patients owing to, for example, a need for as many as from 10 times to 20 times of application a day. In addition, in order to alleviate an inflammatory response in the disease involving inflammation in the lacrimal gland, a drug, such as a steroid or ciclosporin, is used, but cannot improve a secretion amount of tears to a normal condition.
In view of the foregoing, a search for tissue stem cells (adult stem cells) of the lacrimal gland has been advanced in order to achieve a stem cell transplantation therapy capable of restoring an impaired lacrimal gland tissue to realize fundamental recovery of the lacrimal gland function. However, tissue stem cells of the lacrimal gland that have an ability to form a lacrimal gland organ have yet to be isolated.
In addition, the inventors of the present invention previously produced a regenerated lacrimal gland germ to be developed into a lacrimal gland from lacrimal gland epithelial cells and lacrimal gland mesenchymal cells derived from a lacrimal gland germ of a mouse embryo by an organ-germ method (Non Patent Literature 1: Nat. Methods 4, 227-230 (2007)), and implanted such regenerated lacrimal gland germ into a site of lacrimal gland loss in a model mouse having its lacrimal gland function impaired, to thereby reveal that a functional lacrimal gland was able to be regenerated (Non Patent Literature 2: Nature Communications 4, 2497 (2013), doi:10.1038/ncomms3497). This method enables lacrimal gland organ regeneration, but in consideration of future clinical application in humans, has had a problem of requiring a technology for deriving a lacrimal gland from a clinically applicable cell source, such as embryonic stem cells (ES cells) or induced pluripotent stem cells (iPS cells). Under such technical circumstances, there has yet to be made a report of successful derivation from ES cells or iPS cells into lacrimal gland epithelial cells or lacrimal gland mesenchymal cells.